Featured Research

from universities, journals, and other organizations

Use It Or Lose It Applies To Nervous System, Scientists Find

Date:

October 18, 1999

Source:

Washington University School Of Medicine

Summary:

For the first time, scientists have monitored the comings and goings of a membrane protein in living animals. They found that a muscle protein that receives messages from nerve fibers skulks away if ignored. This may explain why withdrawal of neuromuscular blocking agents sometimes is fatal to patients who have been on respirators. And it supports the idea that learning involves rapid molecular changes at cellular junctions in the brain.

Share This

St. Louis, Oct. 15, 1999 - For the first time, scientists have monitored the comings and goings of a membrane protein in living animals. They found that a muscle protein that receives messages from nerve fibers skulks away if ignored. This may explain why withdrawal of neuromuscular blocking agents sometimes is fatal to patients who have been on respirators. And it supports the idea that learning involves rapid molecular changes at cellular junctions in the brain.

Related Articles

"Our study shows that activity in the nervous system has a surprisingly rapid effect on the structure of synapses" the structures where nerve cells communicate with their targets," says Jeff W. Lichtman, M.D., Ph.D., head of the research team.

Lichtman is a professor of neurobiology at Washington University School of Medicine in St. Louis. He and his colleagues report their findings in the Oct. 15 issue of Science. Postdoctoral fellow Mohammed Akaaboune, Ph.D., is first author of the paper, which is accompanied by a commentary from Miriam M. Salpeter, Ph.D., of Cornell University.

Neuromuscular synapses connect nerve terminals to muscle fibers. When the nerve terminal releases a chemical signal called acetylcholine, protein molecules on the muscle fiber's surface bind the acetylcholine and initiate a chain of events that lead to muscle contraction. These protein molecules, called acetylcholine receptors, huddle under the nerve terminal so they are in the best place to receive the chemical signal.

For many years, Lichtman's group has used a fluorescent form of bungarotoxin to light up acetylcholine receptors in living animals. This constituent of snake venom permanently combines with the receptors, putting muscles out of action. In 1996, a researcher in Lichtman's lab, Stephen G. Turney, figured out how to use this labeling technique to measure the amount of acetylcholine receptor protein at individual synapses.

In the current study, the researchers determined how receptor concentrations on single muscle fiber cells changed with time. "No one had previously monitored the turnover of membrane proteins in a single cell in a living animal," Akaaboune says. "People tried to understand turnover before, but they were able to do experiments only with cultured cells or, more crudely, by grinding up whole muscles."

The researchers measured the brightness of individual synapses immediately after applying fluorescent bungarotoxin to muscle fibers in a mouse's neck. They located the same synapses hours and then days later to see how much fluorescence - and therefore how much receptor protein - remained.

They expected to see a steady, slow loss of receptors after they applied the bungarotoxin. "We thought the receptors would sit there for an average of nine or 10 days," Lichtman says. "But within two hours, they started leaving in droves."

About 10 percent of the fluorescence disappeared within the first two hours. Then the rate slowed. If the researchers kept adding bungarotoxin, however, the receptors continued their rapid flight from the synapse, spreading into the surrounding membrane. And after eight hours, they were inside the cell, on their way to the garbage disposal.

In the next experiment, the researchers added just enough bungarotoxin to poison only 20 percent of the receptors. This time, they didn't see rapid flight. As long as a muscle fiber still could receive signals from a nerve, its receptors stayed. The researchers then added enough bungarotoxin to silence the synapses, but they electrically stimulated the muscle at the same time. Again, the receptors stayed put. "So muscle activity is a cue to keep a synapse stable, and synaptic inactivity is a cue to disassemble a synapse," Lichtman says.

In a further experiment, the researchers used a small dose of bungarotoxin to label only some of the receptors. Then they added curare, which poisons acetylcholine receptors but can be washed out. After four hours, every synapse had lost its fluorescence. But after the curare was removed, every junction got brighter again as fleeing receptor protein molecules turned around and re-clustered at the synapse. "So if you lose activity, you lose receptors. But if you regain activity, you get those receptors back," Lichtman says.

The synaptic region of a muscle fiber contains a protein scaffold that holds acetylcholine receptors in place. The researchers suggest that loss of nerve signals loosens this scaffold, allowing receptors to escape. When the muscle becomes active again, the scaffold tightens its grip, catching any receptors that come by.

This dynamic picture may be relevant to the brain. Many neuroscientists believe that learning involves changes at neuron-to-neuron synapses. Such changes, called long-term potentiation or LTP, make it easier for connected neurons to communicate with each other and therefore for memories to form. Because receptor aggregation may contribute to LTP and dispersal may contribute to the reverse scenario, long-term depression, the discovery that receptors can scurry in and out of synapses strengthens the synaptic hypothesis of learning. "It comes as a surprise that the stable, stupid neuromuscular junction of mammals, where no one would consider that learning is taking place, has a very similar mechanism to the one that is thought to alter the strength of synapses in the brain," Lichtman says. "Therefore we'll be able to study the underlying mechanism in the accessible neuromuscular synapse."

The team's discovery also may explain why about 5 percent of patients who receive neuromuscular blocking agents while on respirators remain paralyzed when these drugs are discontinued. "These agents silence the neuromuscular junction just as bungarotoxin silenced it in our mice," Lichtman says. "So after several days, the receptors will be lost. When the synapse starts working again, there won't be enough of them to activate muscles, and the patient will remain paralyzed. Our results suggest that stimulating muscles while giving these drugs might save some lives."

Washington University School Of Medicine. "Use It Or Lose It Applies To Nervous System, Scientists Find." ScienceDaily. ScienceDaily, 18 October 1999. <www.sciencedaily.com/releases/1999/10/991018080148.htm>.

Washington University School Of Medicine. (1999, October 18). Use It Or Lose It Applies To Nervous System, Scientists Find. ScienceDaily. Retrieved March 3, 2015 from www.sciencedaily.com/releases/1999/10/991018080148.htm

Washington University School Of Medicine. "Use It Or Lose It Applies To Nervous System, Scientists Find." ScienceDaily. www.sciencedaily.com/releases/1999/10/991018080148.htm (accessed March 3, 2015).

More From ScienceDaily

More Mind & Brain News

Featured Research

Mar. 3, 2015 — The literary great Marcel Proust wore ear-stoppers because he was unable to filter out irrelevant noise -- and lined his bedroom with cork to attenuate sound. Now new research suggests why the ... full story

Mar. 3, 2015 — Attendance at schools exposed to high levels of traffic-related air pollution is linked to slower cognitive development among 7- to 10-year-old children in Barcelona, according to a new ... full story

Mar. 3, 2015 — No significant change in home habits of smokers have been observed in the aftermath of a ban on smoking in public spaces, researchers report. Greater inspiration to kick the habit likely comes from ... full story

Mar. 3, 2015 — Heart function has been associated with the development of dementia and Alzheimer's disease through a new study. Participants with decreased heart function, measured by cardiac index, were two to ... full story

Mar. 3, 2015 — Children of recently separated or divorced families are likelier to drink sugar-sweetened beverages than children in families where the parents are married, putting them at higher risk for obesity ... full story

Mar. 3, 2015 — Although sedatives are often administered before surgery, a randomized trial finds that among patients undergoing elective surgery under general anesthesia, receiving the sedative lorazepam before ... full story

Mar. 3, 2015 — Why do people shake hands? A new study suggests one of the reasons for this ancient custom may be to check out each other's odors. Even if we are not consciously aware of this, handshaking may ... full story

Mar. 3, 2015 — It appears that stress markers in unemployed people can be found, independent of smoking, alcohol consumption and overweight/obesity. Results from a study suggest that long-term unemployment may be ... full story

Mar. 3, 2015 — On the heels of an American nationwide measles outbreak comes a report that campaigns aimed at scaring people about the consequences of non-vaccination might not be as effective as many think. ... full story

Mar. 3, 2015 — Doctors write millions of prescriptions a year for drugs to calm the behavior of people with Alzheimer’s disease and other types of dementia. But non-drug approaches actually work better, and carry ... full story

Related Stories

Nov. 11, 2014 — Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis, or ALS, might damage muscle-controlling nerve cells in the brain earlier in the disease process than previously known, according ... full story

July 11, 2012 — Communication between the brain and muscle must be strong for us to eat, breathe or walk. Now scientists have found that a protein known to be on the surface of muscle cells must be present in both ... full story

Feb. 8, 2012 — Some unusual alliances are necessary for you to wiggle your fingers, researchers report. Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia ... full story

Dec. 20, 2010 — Researchers have "engineered" a mouse that can run on a treadmill twice as long as a normal mouse by increasing its supply of acetylcholine, the neurotransmitter essential for muscle ... full story

Aug. 2, 2010 — Researchers have uncovered a mechanism through which caloric restriction and exercise delay some of the debilitating effects of aging by rejuvenating connections between nerves and the muscles that ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.